营养压力条件下cMyc通过丝氨酸合成通路促进肿瘤的发生发展

发布时间：2018-07-13 11:06

【摘要】：实体瘤增殖过程中,肿瘤细胞往往处于低氧、营养匮乏、氧化应激等应激微环境中。肿瘤细胞如何适应这样的微环境而生存是多年来研究者所关注的一个重要问题。在营养匮乏的微环境下,肿瘤细胞会通过代谢改变等来促进细胞的增殖和存活。因此,解析肿瘤细胞如何适应营养匮乏微环境而生存的分子机制对理解肿瘤发生发展并靶向治疗肿瘤非常重要。糖和谷氨酰胺是肿瘤细胞赖以生存的两大重要能源物质。我们发现糖或谷氨酰胺缺失的应激处理将促使肿瘤细胞的多种代谢通路发生改变,其中最重要的一种改变是丝氨酸合成通路(Serine Synthesis Pathway,SSP)的激活。我们发现营养缺失压力条件下,原癌基因cMyc活性增强,从而在转录水平上激活SSP代谢通路中的多种代谢酶,特别是PSPH (phosphoserine phosphatase)这一丝氨酸代谢的限速酶,导致SSP代谢的加强。而SSP通路的活化则可以通过调控氧化还原稳态、细胞周期以及核苷酸的合成来支持肿瘤细胞在营养压力条件下的存活。临床样本研究也证实SSP通路酶的高表达与临床肝癌病人的预后成明显的负相关。因此,本研究不仅揭示了肿瘤细胞激活SSP代谢通路而适应营养匮乏这种应激微环境的分子机制,还为临床肝癌的诊断及治疗提供了新的潜在靶点。
[Abstract]:In the process of solid tumor proliferation, tumor cells are often in stress microenvironment such as hypoxia, nutritional deficiency, oxidative stress and so on. How tumor cells adapt to such microenvironments and survive has been an important issue for many years. In the nutrient deficient microenvironment, tumor cells promote cell proliferation and survival through metabolic changes. Therefore, it is important to understand the molecular mechanism of how tumor cells adapt to the microenvironment of nutritional deficiency to understand tumor development and target tumor therapy. Sugar and glutamine are two important energy sources for the survival of tumor cells. We have found that stress treatment with glucose or glutamine deficiency may induce changes in many metabolic pathways in tumor cells, the most important of which is the activation of Serine Synthesis PathwaySSP (Serine Synthesis PathwaySSP). We found that the activity of proto-oncogene cMyc was increased under the stress of nutrient deficiency, thus activating many metabolic enzymes in the SSP metabolic pathway at the transcriptional level, especially PSPH (phosphoserine phosphatase), the rate-limiting enzyme of serine metabolism, which led to the enhancement of the metabolism of SSP. The activation of SSP pathway can support the survival of tumor cells under nutritional stress by regulating redox homeostasis cell cycle and nucleotide synthesis. The high expression of SSP pathway enzyme was negatively correlated with the prognosis of HCC patients. Therefore, this study not only revealed the molecular mechanism of tumor cells activating SSP metabolic pathway to adapt to the stress microenvironment of nutritional deficiency, but also provided a new potential target for clinical diagnosis and treatment of liver cancer.
【学位授予单位】：中国科学技术大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R730.231

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